Impact of COVID-19 versus other pneumonia on in-hospital mortality and functional decline among Japanese dialysis patients: a retrospective cohort study

Coronavirus disease 2019 (COVID-19) affects both life and health. However, the differentiation from other types of pneumonia and effect of kidney disease remains uncertain. This retrospective observational study investigated the risk of in-hospital death and functional decline in ≥ 20% of Barthel Index scores after COVID-19 compared to other forms of pneumonia among Japanese adults, both with and without end-stage kidney disease (ESKD). The study enrolled 123,378 patients aged 18 years and older from a national inpatient administrative claims database in Japan that covers the first three waves of the COVID-19 pandemic in 2020. After a 1:1:1:1 propensity score matching into non-COVID-19/non-dialysis, COVID-19/non-dialysis, non-COVID-19/dialysis, and COVID-19/dialysis groups, 2136 adults were included in the analyses. The multivariable logistic regression analyses revealed greater odds ratios (ORs) of death [5.92 (95% CI 3.62–9.96)] and functional decline [1.93 (95% CI 1.26–2.99)] only in the COVID-19/dialysis group versus the non-COVID-19/non-dialysis group. The COVID-19/dialysis group had a higher risk of death directly due to pneumonia (OR 6.02, 95% CI 3.50–10.8) or death due to other diseases (OR 3.00, 95% CI 1.11–8.48; versus the non-COVID-19/non-dialysis group). COVID-19 displayed a greater impact on physical function than other types of pneumonia particularly in ESKD.


Patient characteristics
The Barthel Index scores at admission and discharge were calculated based on 10 functional abilities: feeding, bathing, dressing, grooming, toileting, bowel control, bladder control, chair transfer, ambulation, and climbing stairs 21 .The Barthel Index ranges from 0 to 100 points, with the highest scores indicating greater independence in physical functions and lower scores indicating a more bedridden status.The Barthel Index scores were used to classify the level of dependence into four groups: total dependence (0-20 points), severe dependence (21-60 points), moderate dependence (61-90 points), and mild dependence or complete independence (91-100 points) 22,23 .In addition, other clinical data on inpatients were collected, including age, gender, BMI, dialysis dependency, the updated Charlson Comorbidity Index excluding renal disease 20,23 , comorbidities, and admission type (emergency or non-emergency).The age groups used in the analysis were 18-49, 50-59, 60-69, 70-79, and greater than 80 years 24 .

Outcomes
The primary outcome of this study was the occurrence of in-hospital deaths from any cause.The secondary outcome was a decline in physical function, defined as a decrease of at least 20% in the Barthel Index score at discharge compared to that at admission.We also evaluated a risk of death directly from pneumonia or death due to other diseases.The database identified deaths from COVID-19 or non-COVID-19 pneumonia as a primary diagnosis during hospitalization or those from other reasons.Other outcomes included hospital length of stay and medical care cost.The long-term hospitalization was defined as a stay of 30 days or longer.The high medical cost was defined as the highest quartile of participants.Patients were followed until discharge, transfer, or in-hospital death 20 . www.nature.com/scientificreports/

Data analyses
Baseline characteristics were presented as numerical values (%) or medians (interquartile ranges).The Wald confidence interval for proportions was examined.We estimated the propensity score using a logistic regression model.To minimize potential confounding effects, differences in age (18-49, 50-59, 60-69, 70-79, and greater than 80 years) and sex were adjusted.Based on the propensity score using a 1:1 scheme, Non-COVID-19/D patients (prematching, N = 1894; postmatching, N = 534) were first matched with COVID-19/D patients (prematching, N = 660; postmatching, N = 534).Subsequently, COVID-19/ND (prematching, N = 54,132; postmatching, N = 534) and Non-COVID-19/ND patients (prematching, N = 66,692; postmatching, N = 534) were adjusted with each COVID-19/D patient.The caliper width used for matching was set at 0.25 of the standard deviation of the propensity score.The cumulative hazard after hospitalization for pneumonia was assessed using the Nelson-Aalen estimator among the four groups.The log-rank test was used for a statistical comparison.Risks of mortality or functional decline were estimated using logistic regression analyses among postmatching patients, adjusting for age, gender, BMI, Barthel Index score at admission, and Charlson Comorbidity Index score.Statistical analyses were performed using JMP Pro 12.0 software (SAS Institute Inc., Cary, USA).p-values of less than 0.05 were considered statistically significant.

Patient characteristics
The characteristics of the dialysis and non-dialysis patients hospitalized with COVID-19 or non-COVID-19 pneumonia (n = 123,378) in Japan during 2020 are listed in Table S1.Before PSM, the prematching patients had an age ranging from 56 to 80 years, a percentage of women ranging from 22 to 43%, and a BMI ranging from 21 to 23 kg/m 2 .After PSM, a total of 2136 patients were divided into four subgroups, each consisting of 534 patients: non-COVID-19/ND, COVID-19/ND, non-COVID-19/D, and COVID-19/D (Table 1).The median age for each subgroup was 69 years, with the percentage of women ranging from 26 to 27% and a BMI ranging from 21 to 24 kg/m 2 .In comparison to the COVID-19 group, the non-COVID-19 group exhibited lower Barthel Index scores.The patients with non-COVID-19 pneumonia had higher proportions of cardiovascular disease and higher Charlson Comorbidity Index scores than the patients with COVID-19.Furthermore, Charlson Comorbidity Index scores were higher in the dialysis group than in the non-dialysis group.
The logistic regression models adjusting for diabetes mellitus instead of Charlson Comorbidity Index showed the similar odds of death and functional decline in the COVID-19/D group (Fig. S2).To further examine the risks of earlier or later deaths, we performed logistic regression analyses for a risk of overall death within 20 days or ≥ 21 days after hospitalization.As a result, the COVID-19/D group was at a greater risk of overall death within 20 days and ≥ 21 days after admission (Fig. S3a).

Risk of in-hospital death primarily due to pneumonia or other comorbidities among non-COVID-19/non-dialysis, COVID-19/non-dialysis, non-COVID-19/dialysis, and COVID-19/ dialysis patients
To assess whether the causes of death were directly attributed to pneumonia or diseases other than pneumonia, the primary reasons for in-hospital mortality were examined in each group.Figure 3 shows the ORs for direct causes of in-hospital mortality due to pneumonia and other comorbidities.It was found that the non-COVID-19/D and COVID-19/D groups on chronic dialysis were more likely to die due to causes other than pneumonia (OR 2.55; 95% CI 1.12-6.29;OR 3.00, 95% CI  S3b).These findings suggest that patients on dialysis are more likely to develop severe pneumonia and subsequent comorbidities under the COVID-19 condition, but not under other types of pneumonia.
To investigate the relationship between hospital stay and outcomes, the length of hospitalization and medical expenses were examined.As shown in Fig. S4, patients on dialysis in the COVID-19/D and non-COVID-19/D groups had a higher risk of long-term hospitalization (OR 1.61, 95% CI 1.11-2.34,p < 0.013 and OR 1.37, 95% CI 0.96-1.96,p = 0.085, respectively).In contrast, the COVID-19/ND group had a significantly lower risk of longterm hospitalization (OR 0.51, 95% CI 0.32-0.82,p < 0.0054).The increased comorbidities and isolation period might contribute to longer hospital stays for patients on dialysis.Logistic regression analyses were also performed to assess the risk of high medical costs, defined as the highest quartile of participants.Notably, the COVID-19/D group was found to be associated with higher medical costs (OR 13.2, 95% CI 9.18-19.1,p < 0.0001).

Table 1.
Characteristics of patients hospitalized with pneumonia in Japan during 2020.Data are presented as numbers (percentages) or medians (interquartile ranges).To compare the four groups, one-way analysis of variance was used for continuous variables, while a chi-squared test was used for categorical variables.D dialysis, non-COVID-19 non-COVID-19 pneumonia.a ND was defined as non-dialysis patients.group compared to the non-COVID-19/ND group, the risks for functional decline were comparable between the two groups.Notably, the COVID-19/D group demonstrated the highest risks of a hospital stay of 30 days or longer and functional decline compared to the other three groups.
The SARS-CoV-2 variants of concern were B1.1.7 (or alpha) and B.1.351(or beta) during 2020.The initial Japanese study conducted in 2020 revealed that the crude mortality rate attributed to COVID-19 in patients on dialysis was 20 times higher than that in the general population 25 .The findings were consistent with reports from the United States and Europe, which also reported an increased risk of death from COVID-19 in patients on dialysis compared to non-dialysis patients 14,26 .The present study further demonstrated that dialysis patients with non-COVID-19 and COVID-19 pneumonia exhibited a higher risk of mortality than non-dialysis patients.These findings align with previous studies reporting that patients on dialysis are immunocompromised 8,27 .Notably, the mortality risk associated with COVID-19 was much greater than that for other types of pneumonia in patients with ESKD.Regarding the direct causes of death, the mortality risks due to diseases other than pneumonia were similarly higher in both the COVID-19/D and non-COVID-19/D groups than in the ND groups.This finding is consistent with previous studies highlighting the complex nature of disease and the presence of multiple comorbidities in patients with ESKD 28 .It is noteworthy that the risk of death directly attributed to pneumonia was not increased in the non-COVID-19/D group, while it was markedly higher in the COVID-19/D group.These findings suggest that COVID-19 leads to more severe pneumonia and comorbidities in patients with kidney diseases compared to other types of pneumonia.
In the present study, an increased risk of decline in ADL was observed in dialysis patients with COVID-19, with approximately twice the odds compared to other groups.This could be attributed to the longer length of hospital stay, which generally leads to a decline in ADL 29 .However, it is worth noting that the increase in the  length of hospital stay was also marginally significant for dialysis patients with non-COVID-19 pneumonia.Furthermore, despite a much shorter hospital stay in the COVID-19/ND group, the risk of ADL decline was equally high compared to the non-COVID-19/ND group.These findings suggest that COVID-19 specifically affects the musculoskeletal system and physical function during hospitalization more than non-COVID-19 pneumonia.
It has been reported that COVID-19 leads to a decline in ADL 30 .However, the difference in the impact of COVID-19 compared to other types of pneumonia on physical function has not been fully understood.This study is the first to compare this using a nationwide survey with the PSM of the groups.The potential mechanisms for the impact of COVID-19 on physical function include the cytokine storm (e.g., tumor necrosis factor-alpha and interleukin 6) induced by the virus, which may directly cause a decrease in muscle mass and strength by decreasing the synthesis and increasing the degradation of muscle proteins 31,32 .Other factors that may contribute to this decline include myotoxic drugs like steroids and Intensive Care Unit admissions 30 .However, further studies are needed to elucidate the remaining factors and mechanisms in order to develop specific interventions to mitigate the loss of muscle mass, strength, and physical function during COVID-19.
It is possible that the isolation of patients with COVID-19 contributed to the decline in ADL in patients on dialysis.During the earlier waves of the COVID-19 pandemic, early discharge and home recuperation were usually recommended until sufficient evidence was accumulated.In contrast, dialysis patients with COVID-19 presumably required a longer hospital stay because of a need for a hospital-based isolation during dialysis sessions.Due to their underlying frailty, the combination of isolation and the direct impact of COVID-19 pneumonia may have a substantially critical effect on patients on dialysis compared to those with normal kidney function.Early rehabilitation intervention after COVID-19 has been reported to help maintain ADL (17).Currently, there are no guidelines or consensus on early intervention in the acute phase of COVID-19.Our findings may have clinical implications for the isolation protocols of patients with COVID-19 and the implementation of universal precautions, particularly for patients with underlying kidney disease.
The strength of this study lies in its well-validated, large-scale design, which provided a nationally representative sample of the Japanese population.However, there are several limitations that should be acknowledged.First, our study specifically focused on the initial three waves of the COVID-19 epidemic in 2020.It is important to consider that COVID-19 has since undergone multiple mutations, potentially leading to different characteristics compared to the time of our study.Second, the diagnoses of COVID-19 and non-COVID-19 pneumonia were based on the ICD-10 codes.The microbiological diagnosis of pneumonia was not available.Third, the database lacked laboratory data such as blood sampling results, imaging, and oxygen saturation.Information on the use of immunosuppressive agents were also unavailable.
In conclusion, our findings indicate that COVID-19 poses a significant risk of in-hospital mortality and a decline in ADL among patients on dialysis during the initial three waves of the pandemic.This suggests that the specific characteristics of COVID-19, along with the frailty of patients on dialysis and the prolonged isolation measures, may have contributed to these outcomes.The prolonged isolation period due to COVID-19 and the challenges in implementing rehabilitation interventions may contribute to the decline in ADL, particularly among patients receiving maintenance dialysis.These factors should be considered when determining the appropriate duration of isolation for dialysis patients with COVID-19.

Figure 1 .
Figure 1.In-hospital death and decline in physical function after coronavirus disease 2019 (COVID-19) and other types of pneumonia in Japan.(a) The Nelson-Aalen estimator of the cumulative hazard among the non-COVID-19/non-dialysis, COVID-19/non-dialysis, non-COVID-19/dialysis, and COVID-19/dialysis groups within 30 days after hospitalization.A statistical comparison was performed with the log-rank test (p = 0.0001).(b,c) Prevalence of overall in-hospital death (b) and functional decline after survival (c) in each age stratum.Each circle represents a mean, and the solid lines represent the corresponding 95% confidence intervals (CIs) among non-COVID-19/non-dialysis, COVID-19/non-dialysis, non-COVID-19/dialysis, and COVID-19/ dialysis groups.A chi-squared test was used to compare the four groups.The decline in physical function was defined as a 20% or more decline in Barthel Index scores at discharge from admission.CI confidence interval, ND non-dialysis patients, D dialysis, non-COVID-19 non-COVID-19 pneumonia.

Figure 2 .
Figure 2. Risk of in-hospital death and decline in physical function among non-coronavirus disease 2019 (COVID-19)/non-dialysis, COVID-19/non-dialysis, non-COVID-19/dialysis, and COVID-19/dialysis patients.Multivariable logistic regression models were adjusted for age, gender, body mass index, Barthel Index score on admission, and Charlson Comorbidity Index score.Each circle represents a point estimate of odds ratios (ORs), and the solid lines represent the corresponding 95% confidence intervals (CIs).a The decline in physical function was defined as a 20% or more decline in Barthel Index scores at discharge from admission.CI confidence interval, OR odds ratio, ND non-dialysis patients, D dialysis, non-COVID-19 non-COVID-19 pneumonia.